Dr. Polydefkis is a Neurology Fellow at Johns Hopkins. He has spent the past two years training in electrophysiology and neuromuscular disease emphasizing applications of skin biopsy to evaluate small fiber nerves. Through this award, he will conduct patient oriented clinical research as a faculty member in Neurology at Johns Hopkins, pursuing skin biopsy as a novel tool to measure axonal regeneration and to screen neurotrophic agents for potential efficacy. Drs. Griffin and McArthur will comentor the candidate and are experts in the fields of peripheral nerve disease, and epidemiology and clinical trial design respectively. The candidate will also complete formal training in clinical investigation and peripheral nerve regeneration. The search for agents to promote axonal regeneration in diabetic neuropathy has been met with frustration. A pattern has emerged in which neurotrophic compounds appear promising in animal models yet fail to fulfill that promise in human trials. A consensus has emerged that novel approaches and outcome measures are needed. The purpose of this study is to develop standardized, human nerve injury models in epidermal nerve fibers. Regenerative capacity in response to these standardized nerve injuries will be developed as an outcome measure. This approach has several advantages: the biopsy technique is noninvasive, able to detect mild neuropathy and can be repeated to follow changes over time. Dr. Polydefkis has developed techniques to measure both regenerative and collateral sprouting of epidermal nerve fiber axons. Regenerative sprouting is determined through reinnervation of skin following chemical axotomy achieved by the topical application of capsaicin. Collateral sprouting is assessed by the growth of epidermal nerve fibers from the margins of a biopsy site into the healed biopsy site. These models will allow comparison of the regenerative capacity in diabetics and healthy controls. Since the reinnervation measured through our models occurs in a timely fashion, they are ideally suited to the application as novel outcome measures to assess the efficacy of neurotrophic agents in diabetic neuropathy trials. The combination of research utilizing established laboratory techniques; the excellent mentorship of senior scientists, and the supportive environment of the Johns Hopkins University will provide Dr. Polydefkis the skills he needs to develop into an independent clinician researcher in the field of peripheral nerve disease.